Dr. Randy Schatzman, CEO, Bolt: Developing Novel Cancer Immunotherapeutics

Bolt Biotherapeutics stands as a company dedicated to cancer immunotherapeutics and myeloid biology. Spearheaded by leaders in immuno-oncology drug discovery and development, they aim to develop and commercialize treatments that address unmet needs in cancer patients.

DocWire News spoke with Randall Schatzman, PhD, CEO of Bolt, who talked about the company and its vast capabilities.

DocWire News: Can you provide us with some background on yourself?

Dr. Randy Schatzman: Yeah. My background is, I’m trained as a biochemist and a pharmacologist, and pharmacology is the study of the interaction of drugs with the human body. And in that training program our department chairman insisted that if we were going to make drugs that ultimately physicians would use to treat their patients, then we should train the way physicians do. So I took the first two years of medical school alongside of training physicians. And when they went to the clinical, ultimately I went to the laboratory to investigate new drugs.

Since that time I’ve been involved with a couple of companies, both large and small. Most recently I was a co-founder of a biotechnology company based in Seattle, where we were using antibody therapeutics in this case to treat migraine patients for their migraines. And ultimately that drug that came out of that is now on the market, it’s known as Vyepti and the company was acquired a couple of years back by Lundbeck.

Bolt was founded in 2015 with the goal of developing cancer immunotherapeutics. Can you tell us more about the company and its vision?

Yeah, so what Bolt is about is really changing the way cancer therapies are used to treat cancers today. And what I mean by that is we’re aiming to treat and eliminate the most difficult solid cancers that today are really unaddressed, and included amongst those are colorectal, lung cancer and pancreatic cancer that have just been extremely difficult for physicians to treat.

And so the reason that cancers happen to begin with is that cancer cells evolve in ways to evade the body’s immune system. So the immune system is not able to recognize these cells as foreign invaders. And so what we’re doing at Bolt is really hijacking the system by which the body uses to surveil for these foreign invaders and reveal those cancers to the immune system. So actually it’s a patient’s own immune system that actually wakes up, recognizes and eliminates their own cancer, is what the technology does.

Bolt’s lead technology is the Boltbody immune-stimulating antibody conjugate (ISAC) platform. Can you tell us about ISACs? How do they train the immune system to fight cancer?

Yeah. This is a new class of what we call a targeted immunotherapy. The agent itself, as you said, is called the ISAC, or immune stimulating antibody conjugate. And simply put, this is a tumor targeting antibody which we use essentially as the missile to direct a warhead to a tumor to activate the immune system. The warhead, in this case, we directly couple to that antibody so that it’s delivered into the tumor micro environment.

And then that warhead is really a potent stimulator of the bodies innate and adaptive immune systems. So by using that warhead to activate what’s really the most primitive side of the body’s immune system, and that’s the side of the immune system that’s really about looking out and surveilling for foreign invaders. What we’re able to do is, as I said earlier, hijack that system and use it to identify the tumor as a foreign invader to the immune system, and ultimately have the immune system eliminate it.

Your most advanced therapy, BDC-1001, is a treatment for HER2 positive cancers. What led you to start with this target?

The reason we chose this is that the targeting antibody in this case is a well-known treatment for breast cancer and it’s called trastuzumab. And so we use that antibody really as a GPS signal to target our payloads to tumors that express HER2 on the surface of their cells. In this case, the antibody isn’t doing much other than directing the payload into the tumor itself. This was really an exercise in understanding the payload and what it did, as opposed to having novel antibody, novel target on the cancer cell, as well as a novel approach to stimulating the immune system. So it’s really breaking down the problem of how our mechanism action works and really identifying the key steps along the way.

What is your myeloid modulator program? How does it differ from the ISAC Boltbody platform?

Yeah. As you know, myeloid cells are an important component of the innate immune system, and they’re recruited into areas where foreign targets have invaded the human body. And what the myeloid cell does is it actually engulfs and destroys that foreign invader. And so we’re using that as a mechanism to recognize and destroy cancers in this case. With our ISAC programs, we use a payload on the antibodies to activate the myeloid cell. With our targeted program that’s actually modulating myeloid cells in a different way, the target is a surface receptor on these myeloid cells that we call Dectin-2.

And what Dectin-2 allows us to do, again, is stimulate these myeloid cells, get them to recognize the tumor and eliminate it. And importantly, what it does is it takes a tumor resident macrophage, in this case, that is what we call tumor supportive. Meaning it’s function has really been about helping the tumor grow, and we’re able to change and reprogram its phenotype into what we call a tumor destructive phenotype. So it recognizes, engulfs and destroys the tumor cells. And directly stimulating this receptor known as Dectin-2 allows us to do that.

Bolt has announced several partnerships in recent years. How do these contribute to the company’s overall strategy?

Yeah, partnerships for us are important in three ways. I mean, first and foremost, it allows us to access novel technologies that we believe will become what we call the next generation of ISACs for treating cancer, and the Genmab relationship is a good example of that. The second reason that we partner is to gain access to our partners’ antibodies for targeting our payloads, or to maybe proprietary targets that they have that we think will be important in treating some of these difficult to solve tumors. The Innovent program is a good example of that. And then finally, partnering for us is about getting revenues. This is a way to support what we call the Bolt in-house pipeline of agents that we’re advancing, and its important cash to be able to do that.

Any closing thoughts?

Yes, I think what we would like your listeners to understand is that we see the Bolt technology really as a game-changer. While we were retraining the immune system to recognize and kill cancers, interestingly the other thing that it does is it leaves the host with what we call an immunologic memory of their cancer. Such that should that cancer come back, which they often do, the immune system will continue to recognize and eliminate that cancer without retreatment.

And this is very different from the way we treat cancer today. Typically, once we get a patient into remission with today’s therapies, when that cancer comes back we have to retreat them with some very toxic drugs and they have to endure that retreatment. The Bolt technology is aimed at relieving and not requiring that retreatment.